The proposed study will rapidly identify and access many motivated women with breast cancer and their parents, and can effectively use the DNA and environmental data now being collected from their unaffected sisters. The study gains enormous operational efficiency advantages, by taking advantage of the infrastructure that is already in place and functioning smoothly for the Sister Study (Dale Sandler, PI). Based on the first 10,000 Sister Study enrollees, more than 20% have an eligible sister and 80% of those have one or both parents living. Mail-back saliva kits will provide DNA from cases and parents. We will collect clinical data and validate the diagnoses for all 1,600 cases. Follow-up of these cases (through the Sister Study will also allow us to identify environmental, clinical, and genetic factors that influence health after treatment. We plan to genotype 1,536 markers on some 150 candidate genes, including some expected to be related to risk and others expected to be related to prognosis. In addition, archived DNA will provide a resource for future tests of not-yet-known candidates identified in recently-published and ongoing whole genome scans. Case-parent analyses of gene variants are protected against bias due to confounding by genetic heritage, and also permit detection of both maternally-mediated genetic effects and parent-of-origin (imprinting) effects. In the proposed study, the participating affected sisters will complete a computer-assisted telephone interview like the one their sister will have completed, providing information about personal exposures, reproductive history, and past occupational exposures. Environmental effects will be identifiable through a paired comparison of affected and unaffected sisters. Gene-by-exposure interactions will be assessed with novel statistical methods. In summary, the proposed study leverages off the ongoing Sister Study to build a cost-effective, powerful, and statistically independent study of young-onset breast cancer. This year we designed the study, developed the materials required, and applied for and were awarded foundation funding ($1.7M) to carry it out, through the Susan G. Komen for the Cure foundation. We are now refining recruitment strategies and preparing the package to apply for IRB clearance and OMB approval to put the study into the field, with assistance from the EB support services contract.